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Left behind by reform: the case for improving primary care and mental health system services for people with moderate mental illness.

In this paper, we present a case for improving services to meet the needs of people with moderate mental illness (MMI). We begin by outlining the evolution of mental health reform and its current tendency toward excluding this population. We offer a working definition for MMI and systematically explain why individuals with moderate mental illnesses deserve increased attention and resources within both the mental health system and general medical settings. Some of the 'best practices' on a strategic programme level that can be used to serve people with MMI most effectively are discussed. Making MMI a priority involves reorienting clinical as well as programmatic approaches to address the needs of the population with these disorders. Systems-level financial, structural and manpower supply issues are crucial; challenging government to become a key player in developing a more collaborative model of physical and mental health care. Private health and mental health organisations, professional groups and individual users of services must also commit themselves to recognising the problem of MMI and respond to it more effectively.

Cost-Benefit Analysis↗

[Intensive Naikan therapy for generalized anxiety disorder and panic disorder: clinical outcomes and background].

OBJECT: Intensive Naikan therapy (INT) is used to treat irrational recognition, and to develop awareness of others and self-reflection. Several reports have also shown that INT is effective for treating anxiety disorders. The purpose of the present systematic study was to investigate the factors contributing to the efficacy and clinical outcomes of INT by assessing the background, psychological evolution, and treatment required after such therapy. METHOD: Twenty-eight anxiety disorder inpatients at Tottori University Hospital, 15 with general anxiety disorders (GAD) and 13 with panic disorders (PD), were treated with INT. Age, sex, duration of the present anxiety episode, and diagnosis were investigated. The Tokyo University Egogram (TEG), Yatabe-Guilford personality inventory (YG test) and Rosenzweig picture frustration (PF) study were conducted before and after INT to investigate psychological changes. The long-term efficacy of INT for PD and GAD was assessed with Global Assessment of Functioning (GAF). Whether the patients achieved awareness of others, awareness of egocentricity, feelings of love, and self reflection after INT were investigated. RESULTS: 1) All patients showed improved GAF; the average GAF score increased from 51 +/- 8 (before Naikan therapy) to 83.2 +/- 15 (after therapy). The clinical outcomes of INT were as follows: 17 patients showed extremely effective results (60.7%), 6 were effective (21.4%), 3 were slightly effective (10.7%), and 2 were unchanged (7.1%). Overall, 23 patients (82.1%) showed remarkable improvements as a result of INT (improved group) and 5 showed no remarkable improvements (not improved group). 2) The improved group included significantly more patients with obsessive tendencies or nervous personalities such as a premorbid personality. In addition, significantly more of the patients in this group underwent daily INT and improved more rapidly in the short-term. 3) According to the STAI (state trait anxiety inventory), both state-(S-anxiety), and trait-anxiety (T-anxiety) significantly decreased after INT. The PD group showed significantly reduced S and T-anxiety, but the GAD group only showed significantly reduced T-anxiety. The adult (A) and free child (FC) TEG scales significantly increased, and according to YG, nervousness (N) and depression (D) significantly decreased while general activity (G) and social extraversion (S) significantly increased. Furthermore, according to the PF study, extraggression (E -A) after INT significantly decreased and imaggression (I-A) significantly increased. In the improved group, significantly more patients became more aware of their partners (Naikan) and achieved an objective outlook, awareness of egocentricity, feelings of love and self-reflection after INT. CONCLUSIONS: Our results suggest that INT for PD and GAD is extremely effective, and a very important form of psychotherapy. Attainment of self-reflection caused psychological changes that motivated the patients to continue Naikan therapy daily. We consider this a key factor in maintaining the efficacy of INT.

Adolescent↗

[Choledocal cyst: analysis of 29 cases and review or the literature].

UNLABELLED: The aim of the present study has been to systematize the clinical presentation of the entity named choledochal cyst, in relation with its probable etiopathology and the intraoperative findings as well as its evolution after surgery, based on the revision of the literature and of our experience in 29 cases. MATERIAL AND METHODS: 29 cases of cystic dilatation of the biliar duct extra and/or intrahepatic are analyzed. In 4 cases the diagnosis was prenatal and two were excluded of the study after it has been confirmed they suffered biliary atresia type I. In the left 27 cases, 19 variables are analyzed retrospectively, like age, sex, weight, symptoms, ultrasonographic images, etc. Subsequently, intra-operative cholangiographic findings were correlated with the clinic presentation and the evolution of the patients after surgery. RESULTS: Of the 27 cases analyzed 16 (59,25%) were cystic dilatations from which 14 had a neonatal or early clinic presentation (before 2 years), however the fusiform dilatations were presented later on. From the analyzed symptoms, in relation with the age only the pain and the jaundice showed significant differences, being the pain most frequent in later presentation ande the jaundice in the early form. The two cases of type 3 of Todani or choledochocele were of later presentation. An anomaly in the bilionpacreatric junction was detected in 15 patients; the majority had a later presentation, associated to pancreatitis in 4 cases. Primary cyst excision and biliary Roux-en-Y reconstruction was the treatment of election in the majority of cases. In 3 cases we used the appendix to replace the choledocus, but all three cases were reconverted two years later because of permanent elevation of ALT and GGT. CONCLUSIONS: In favour of the literature and of our experience nowadays it would be possible to systematize this malformation and make a division in two groups, depending on the cholangiographic findings and clinical presentation: 1. Cystic dilatations with a clinical neonatal presentation or beneath 2 years. 2. Fusiform dilatations with a later clinical predominance and associated frequently to pancreatitis and anomalous pancreatobiliary junction. Choledochocele is an entity that must be considered not only for its etiology but for its clinical presentation and treatment. Primary cyst excision and biliary Roux-en-Y reconstruction is the treatment of election. Regular long-term review of these patients is mandatory in the surveillance of sub-clinic cholangitis and the risk of possible long-term malignance of this entity.

Choledochal Cyst↗

[Envenomation by Echis Carinatus in Africa: clinical study and evolution. Indications for antivenins].

In North Cameroon, venom inoculations by Echis Carinatus are frequent and severe and thus pose a serious problem at Public Health Services. 48 bites without antivenomous serum injection have been considered in Garoua, Benoue valley North Cameroon. Without antivenomous serum light inoculations heal spontaneous by in a couple of days about 20% of the average clinical forms are evoluting insidiously to severe globulolysis. The great majority of severe inoculations lead to dreadful hemorrhagic threatening the life of patients. New borns and infants are particularly exposed, it is not advisable to inject systematically antivenomous serum. But it has to be considered as compulsory in the three following clinical situations before 11 years of age, venom inoculation often brings about fast aggravation, mainly in new borns, after 11 years and at adult age, when clinical signs are of great concern, when hemoglobinometry indicates less than 9 gr/100 ml after 48 hours of evolution in youngs and adults, but without any symptom of severity.

Adolescent↗

Evolutionary divergence of exon flanks: a dissection of mutability and selection.

The intronic sequences flanking exon-intron junctions (i.e., exon flanks) are important for splice site recognition and pre-mRNA splicing. Recent studies show a higher degree of sequence conservation at flanks of alternative exons, compared to flanks of constitutive exons. In this article we performed a detailed analysis on the evolutionary divergence of exon flanks between human and chimpanzee, aiming to dissect the impact of mutability and selection on their evolution. Inside exon flanks, sites that might reside in ancestral CpG dinucleotides evolved significantly faster than sites outside of ancestral CpG dinucleotides. This result reflects a systematic variation of mutation rates (mutability) at exon flanks, depending on the local CpG contexts. Remarkably, we observed a significant reduction of the nucleotide substitution rate in flanks of alternatively spliced exons, independent of the site-by-site variation in mutability due to different CpG contexts. Our data provide concrete evidence for increased purifying selection at exon flanks associated with regulation of alternative splicing.

Alternative Splicing↗

Swaps in protein sequences.

An important question in protein evolution is to what extent proteins may have undergone swaps (switches of domain or fragment order) during evolution. Such events might have occurred in several forms: Swaps of short fragments, swaps of structural and functional motifs, or recombination of domains in multidomain proteins. This question is important for the theoretical understanding of the evolution of proteins, and has practical implications for using swaps as a design tool in protein engineering. In order to analyze the question systematically, we conducted a large scale survey of possible swaps and permutations among all pairs of protein from the Swissport database. A swap is defined as a specific kind of sequence mutation between two proteins in which two fragments that appear in both sequences have different relative order in the two sequences. For example, aXbYc and dYeXf are defined as a swap, where X and Y represent sequence fragments that switched their order. Identifying such swaps is difficult using standard sequence comparison packages. One of the main problems in the analysis stems from the fact that many sequences contain repeats, which may be identified as false-positive swaps. We have used two different approaches to detect pairs of proteins with swaps. The first approach is based on the predefined list of domains in Pfam. We identified all the proteins that share at least two domains and analyzed their relative order, looking for pairs in which the order of these domains was switched. We designed an algorithm to distinguish between real swaps and duplications. In the second approach, we used Blast to detect pairs of proteins that share several fragments. Then, we used an automatic procedure to select pairs that are likely to contain swaps. Those pairs were analyzed visually, using a graphical tool, to eliminate duplications. Combining these approaches, about 140 different cases of swaps in the Swissprot database were found (after eliminating multiple pairs within the same family). Some of the cases have been described in the literature, but many are novel examples. Although each new example identified may be interesting to analyze, our main conclusion is that cases of swaps are rare in protein evolution. This observation is at odds with the common view that proteins are very modular to the point that modules (e.g., domains) can be shuffled between proteins with minimal constraints. Our study suggests that sequential constraints, i.e., the relative order between domains, are highly conserved.

Algorithms↗

What developmental disorders can tell us about the nature and origins of language.

Few areas in the cognitive sciences evoke more controversy than language evolution, due in part to the difficulty in gathering relevant empirical data. The study of developmental disorders is well placed to provide important new clues, but has been hampered by a lack of consensus on the aims and interpretation of the research project. We suggest that the application of the Darwinian principle of 'descent with modification' can help to reconcile much apparently inconsistent data. We close by illustrating how systematic analyses within and between disorders, suitably informed by evolutionary theory-and ideally facilitated by the creation of an open-access database-could provide new insights into language evolution.

Biological Evolution↗

A systems-analytical approach to macro-evolutionary phenomena.

Two sets of evolutionary phenomena find no explanation through current theory. For the static phenomena (such as homology, homonomy, systematic weight, and "Type") there is no causal base, although these principles are responsible for all phenomena of predictable order in the living world. The dynamic phenomena (such as homodynamy, coadaptation, parallel evolution, orthogenesis, Cartesian transformation, typostrophy, hetermorphosis, systemic mutation, and spontaneous atavism) have no causal explanation, although they are responsible for all directed phenomena in macroevolution. These phenomena share one unifying principle which can be explained by a system theory of evolution based on, but extending, the current synthetic theory. This system theory envisages feedback conditions between genotype and phenotype by which the chances of successful adaptation increase if the genetic units, by insertion of superimposed genes, copy the functional dependencies of those phene structures for which they code. This positive feedback of the adaptive speed (or probability) within a single adaptive direction is compensated by negative feedback in most of the alternative directions. The negative feedback operates as selection not be environmental but by systemic conditions developed by the organization of the organism. The consequences are an imitatively organized system of gene interractions, the rehabilitation of classical systematics, the reality of the "natural system," and, in general, the resolution of the contradiction between neodarwinists and their critics, between reductionists and holists, between "a priori" and "a posteriori" views, between idealism and materialism, and between the notions of freedom and of purpose in evolution.

Biological Evolution↗

The anatomy of evidence-based publications: article summaries and systematic reviews. Part I.

The term evidence-based has become a popular phrase in the title of many articles. Some articles discuss the process, whereas others lead readers to believe that evidence-based methodology was used in conducting the research or in presenting a synthesis of the findings, which may not be the case. The purpose of Part I of this two-part report is to define evidence-based decision-making (EBDM), discuss the evolution of the evidence based movement, and to describe the distinguishing characteristics of evidence-based publications. In doing so, articles using an evidence-based format, article summaries found in evidence-based journals and systematic reviews, such as those published by the Cochrane Collaboration, will be presented. Part II reviews the findings from the Cochrane Review on manual versus powered toothbrushing for oral health and discusses the strengths and weaknesses of systematic reviews.

Abstracting and Indexing↗

Molecular insights into the evolution of the family Bovidae: a nuclear DNA perspective.

The evolutionary history of the family Bovidae remains controversial despite past comprehensive morphological and genetic investigations. In an effort to resolve some of the systematic uncertainties within the group, a combined molecular phylogeny was constructed based on four independent nuclear DNA markers (2,573 characters) and three mitochondrial DNA genes (1,690 characters) for 34 bovid taxa representing all seven of the currently recognized bovid subfamilies. The nuclear DNA fragments were analyzed separately and in combination after partition homogeneity tests were performed. There was no significant rate heterogeneity among lineages, and retention index values indicated the general absence of homoplasy in the nuclear DNA data. The conservative nuclear DNA data were remarkably effective in resolving associations among bovid subfamilies, which had a rapid radiation dating back to approximately 23 MYA. All analyses supported the monophyly of the Bovinae (cow, nilgai, and kudu clade) as a sister lineage to the remaining bovid subfamilies, and the data convincingly suggest that the subfamilies Alcelaphinae (hartebeest, tsessebe, and wildebeest group) and Hippotraginae (roan, sable, and gemsbok clade) share a close evolutionary relationship and together form a sister clade to the more primitive Caprinae (represented by sheep, goat, and muskox). The problematic Reduncinae (waterbuck, reedbuck) seem to be the earliest-diverging group of the Caprinae/Alcelaphinae/Hippotraginae clade, whereas the Antilopinae (gazelle and dwarf antelope clade) were always polyphyletic. The sequence data suggest that the initial diversification of the Bovidae took place in Eurasia and that lineages such as the Cephalophinae and other enigmatic taxa (impala, suni, and klipspringer) most likely originated, more or less contemporaneously, in Africa.

Animals↗

Evolution and phylogenetic utility of CAD (rudimentary) among Mesozoic-aged Eremoneuran Diptera (Insecta).

We sequenced nearly the entire carbomoylphosphate synthase (CPS) domain of CAD, or rudimentary, (ca. 4 kb) from 29 species of flies representing all major clades within Eremoneura, or higher flies, and several orthorrhaphous brachyceran outgroups. We compared these sequences with orthologs from Anopheles gambiae and Drosophila melanogaster to assess structure, compositional bias, and phylogenetic utility. CAD is large (6.6+ kb), complex (comprised of three major and myriad minor functional domains) and relatively free of introns, extreme nucleotide bias (except third codon positions), and large hypervariable regions. The CPS domain possesses moderate levels of nonsynonymous divergence among taxa of intermediate evolutionary age and conveys considerable phylogenetic signal. Phylogenetic analysis of CPS sequences under varying methods and assumptions resulted in well-resolved, strongly supported trees concordant with many traditional ideas about higher dipteran phylogeny and with prior inferences from 28S rDNA. The most robustly supported major eremoneuran clades were Cyclorrhapha, Platypezoidea, Eumuscomorpha, Empidoidea, Atelestidae, Empidoidea exclusive of Atelestidae, Hybotidae s.l., Microphoridae+Dolichopodidae, and Empididae s. str. Because CAD is ubiquitous, apparently single copy (at least within holometabolous insects), readily obtained from several insect orders using primers described herein, and exhibits considerable phylogenetic utility, it should have wide applicability in insect molecular systematics.

Animals↗

Biodiversity: molecular biological domains, symbiosis and kingdom origins.

The number of extant species of organisms is estimated to be from fewer than 3 to more than 30 x 10(6) (May, 1992). Molecular biology, comparative genetics and ultrastructural analyses provide new insights into evolutionary relationships between these species, including increasingly precise ideas of how species and higher taxa have evolved from common ancestors. Accumulation of random mutations and large macromolecular sequence change in all organisms since the Proterozoic Eon has been importantly supplemented by acquisition of inherited genomes ('symbiogenesis'). Karyotypic alterations (polyploidization and karyotypic fissioning) have been added to these other mechanisms of species origin in plants and animals during the Phanerozoic Eon. The new evolution concepts (coupled with current rapid rates of species extinction and ignorance of the extent of biodiversity) prompted this analysis of the field of systematic biology and its role in the reorganization of extant species into higher taxa. Two superkingdoms (= Domains: Prokaryotae and Eukaryotae) and five kingdoms (Monera = Procaryotae or Bacteria; Protoctista: algae, amoebae, ciliates, foraminifera, oomycetes, slime molds, etc.; Mychota: 'true' fungi; Plantae: one phylum (division) of bryophytes and nine phyla of tracheophytes; and Animalia) are recognized. Two subkingdoms comprise the monera: the great diverse lineages are Archaebacteria and Eubacteria. The criteria for classification using molecular, ultrastructural and genetic data for this scheme are mentioned. For the first time since the nineteenth century, logical, technical definitions for each group are given with their time of appearance as inferred from the fossil record in the primary scientific literature. This classification scheme, which most closely reflects the evolutionary history, molecular biology, genetics and ultrastructure of extant life, requires changes in social organization of biologists, many of whom as botanists and zoologists, still behave as if there were only two important kingdoms (plants and animals).

Animal Population Groups↗

Congenital lumbosacral lipomas.

Congenital lumbosacral lipomas can be responsible for progressive defects. The general feeling is that tethering of roots, filum, or cord probably explains this evolution, and that untethering of these structures could prevent late deterioration. Like the vast majority of neurosurgeons, we too have routinely and systematically operated on lumbosacral lipomas, even in the absence of neurological deficits. This policy stemmed from our belief that spontaneous neurological deterioration was frequent, recovery from preoperative deficits rare, and surgery both efficient and benign in nature. After 22 years of experience, we felt that it was necessary to review our series of 291 lipomas (38 lipomas of the filum and 253 of the conus) operated on from 1972 to 1994. To reassess the value of prophylactic surgery, we attempted an accurate evaluation of (1) the risk of pathology, (2) the risks involved in surgery, (3) the postoperative outcome with respect to preoperative deficits, and (4) the postoperative outcome in asymptomatic patients at 1 year and at maximum follow-up. Special attention was paid to 93 patients whose postoperative follow-up was more than 5 years (average 8.7, median 8, range 5-23 years). Of these 93 patients, 39 were asymptomatic preoperatively (7 with lipoma of the filum and 32 with lipoma of the conus). Lipomas of the filum and of the conus are entirely different lesions and were studied separately. In 6 cases prenatal diagnosis had been possible. The mean age at surgery was 6.4 years. Low back skin stigmata were present in 89.4% of cases. Preoperative neurological deficits existed in 57% of the patients and were congenital in 22%. Clinical signs and symptoms recorded were pain in 13.3% of the patients and/or neurological deficits affecting sphincter (52%), motor (27.6%) and sensory (22.4%) functions. Deficits were progressive in 22.4% of cases, slowly progressive in 58.8% of these and rapidly progressive in the remaining 41.2%. In 36 patients (13.2%) the lipomas were seen to grow either subcutaneously or intraspinally. Among these patients, 21 were infants, 2 were obese adolescents, and 10 were pregnant women. The metabolism of the fat within the lipomas was studied in 11 patients and found to be similar to that at other sites. Lipomas were associated with various other malformations, either intra- or extraspinal. These associated anomalies were rare in the case of lipomatous filum (5.2%) but frequent with lipomas of the conus, except for intracranial malformations (3.6%). Therapeutic objectives were spinal cord untethering and decompression, sparing of functional neural tissue and prevention of retethering. Procedures used to achieve these goals were subtotal removal of the lipoma, intraoperative monitoring, duroplasty, and sometimes closure of the placode. Histologically, lipomas consisted of normal mature fat. However, 77% of them also included a wide variety of other tissues, originating from ectoderm, mesoderm, or entoderm. This indicates that lipomas are either simple or complex teratomas. The results of the study are as follows. (1) Surgery was easy and safe when performed for treatment of lipomas of the filum (no complications), but difficult and hazardous in the case of lipomas of the conus (20% local, 3.9% neurological complications). (2) All types of deficit could be improved by surgery, which was beneficial in all cases of lipoma of the filum and 50% of cases of lipoma of the conus. (3) In asymptomatic patients long-term surgical results depended on the anatomical type of the lipoma. They were excellent in lipomas of the filum. In lipomas of the conus they were good in the short term but eroded with time. At more than 5 years of follow-up only 53.1% of the patients were still free of symptoms. (4) Reoperations were performed in 16 patients (5.5%), 5 (31.2%) of whom improved postoperatively, while in 7 (43.7%) progression stopped, in 3 (18.7%) deterioration continued and in 1 (6.2%) the condition was wor

Adolescent↗

A bioinformatic analysis of the RAB genes of Trypanosoma brucei.

RAB proteins are small GTPases with vital roles in eukaryotic intracellular transport; orthologous RABs appear to fulfil similar functions in diverse organisms. Trypanosoma brucei spp., the causative organisms of Old World trypanosomiasis of humans and domestic animals, have extremely effective endocytic and exocytic mechanisms that are likely to be involved in maintenance of infection, making study of these systems of importance. Taking advantage of the essential completion of the T. brucei genome, we have re-examined the T. brucei RABs (TbRABs) so far described and identified a total of 16. BLAST searches and phylogenetic analysis show that nine of the TbRABs can confidently be assigned as orthologues or homologues of known RAB proteins from higher eukaryotes, and four more with reasonable probability. The core endocytic pathway is probably similar in complexity to yeast, whilst the early exocytic pathway appears to be more complex than in yeast. Two of the TbRAB family (RAB23 and 28) with clear mammalian orthologues appear to be unusual, and may be involved in nuclear processes and are described in more detail in an accompanying paper. Three TbRABs appear, however, to have no close homologues and may fulfil specialised functions in this organism. The availability of a complete set of TbRABs--which includes orthologues of the RABs responsible for control of the core of the endomembrane system (i.e. RAB1, 2, 4-7 and 11)--provides a first overview of the trafficking complexity that is present within a kinetoplastid parasite. Based on these homologies we suggest a systematic nomenclature for the TbRABs to reflect their functional homologies. This information is of importance both from the perspective of understanding the evolution and diversity of eukaryotic trafficking, but also in providing a framework by which to understand protein processing, trafficking, endocytosis and other related processes in these parasites.

Amino Acid Sequence↗

Innovative advances and clinical applications of cell-free DNA methylation detection technologies.

Advances in DNA methylation detection technologies have promoted disease-related cell-free DNA (cfDNA) analysis. CfDNA methylation profiling has the potential to serve as a promising clinical tool for early disease diagnosis. However, current detection technologies suffer from high costs, complex operational procedures, and insufficient sensitivity for low-input samples. Moreover, the definitive validation of its clinical value still awaits robust evidence from high-quality confirmatory studies. Therefore, this review begins by mapping the historical evolution of cfDNA methylation, followed by a comparison of the traditional approaches and recent breakthroughs in cfDNA methylation analysis. Specifically, this review systematically examines the two major strategies: the ones based on bisulfite-dependent DNA modification and the bisulfite-free methods, including the techniques for whole-genome methylation profiling and methods targeting specific genomic regions. Additionally, to evaluate the clinical application potential of these methods, this review comprehensively describes the details of these technologies, such as sample input requirements and sensing accuracy in detecting clinical samples. The future development of cfDNA methylation detection will focus on clinical translation, integrating technical innovations with the demands for efficient clinical diagnosis. We believe this review will help researchers select methods tailored to sample availability and clinical applicability.

Humans↗